tbuckley/cabot-search huggingface dataset:
Abstract 284: A 3D multicellular <i>in vitro</i> prostate cancer model featuring racially/ethnically diverse PDXs
Authors: Divya Iyer, Andrei Bonteanu, Peter Shepherd, Rick Kittles, Nora Navone, Daniel Harrington, Kristin Bircsak
Journal: Cancer Research (2022)

Abstract Current in vitro prostate cancer (PCa) research tools do not incorporate the complexities of the tumor microenvironment including perfusion, multiple cell types, extracellular matrix (ECM) and 3D-orientation. Additionally, these models lack racial/ethnic (R/E) diversity, failing to address the cancer health disparity (CHD) observed in Black men with PCa who experience double the incidence and mortality rates as compared to White men. Population-based in vitro PCa models that support crosstalk between different cell types will improve our understanding of the underlying mechanisms contributing to this CHD and improve the prediction of drug response in specific populations. Here, we used the high-throughput, perfusion-based microfluidic platform called the MIMETAS OrganoPlate® to culture up to 96 individual, multicellular PCa-on-a-chip cultures in parallel. PCa PDX cells of various R/E were embedded together with E2Crimson-labeled stromal fibroblasts in a migration-permissive hyaluronic acid hydrogel in the gel compartment, alongside an endothelium-lined perfusion channel containing a targeted immune cell population. Using high content imaging, we confirmed the stability and viability of the cultures over 7 days. The cultures maintained a 3D structure with PCa cells and fibroblasts evenly dispersed throughout the height of the gel compartment and a blood vessel-like structure within the perfusion channel. Closer evaluation of the gel compartment revealed a close association between PCa cells and stromal fibroblasts in a core-shell structure with PCa clusters surrounded by fibroblasts. Further, all cells maintained expected expression of phenotypic markers (PCa: epCAM, PSMA; fibroblast: vimentin, endothelium: CD31). For the immune component, medium and cell tracker dye conditions were optimized to support immune cell viability. Over 72 hours, immune cells were monitored, revealing migration of PBMCs through the gel compartment. Finally, the value of the complex, population-based multicellular in vitro model of PCa will be evaluated in a drug screen comparing the system with simple, PCa PDX monocultures. This R/E diverse 3D prostate tumor model will enable the full incorporation of all cell types and ECM into a single model which will better recapitulate population specific PCa and drug response. Citation Format: Divya Iyer, Andrei Bonteanu, Peter Shepherd, Rick Kittles, Nora Navone, Daniel Harrington, Kristin Bircsak. A 3D multicellular in vitro prostate cancer model featuring racially/ethnically diverse PDXs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 284.
Abstract 2979: Elevated<i>NRAS</i>expression as a potential driver of DCIS progression to basal-like invasive breast cancer
Authors: Ze-yi Zheng, Hanan Elsarraj, Yang Hong, Jonathan T. Lei, Meenakshi Anurag, Yichao Shen, Flora Lo, Long Feng, Zifan Zhao, Xiang H. Zhang, Fariba Behbod, Eric C. Chang
Journal: Cancer Research (2022)

Abstract Background: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives a subset of luminal DCIS to transition to basal invasive breast cancers is unclear. Basal-like invasive breast cancers are aggressive and associated with the shortest overall survival and time to distant metastasis. We have previously shown that N-Ras is highly expressed selectively in the basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers. Methods: Wilcoxon rank-sum test was conducted to assess the relative expression of NRAS in DCIS compared to invasive breast cancers in a patient cohort (GSE59248). NRAS levels were also determined by fluorescence in situ hybridization (FISH) in a collection of 21 patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and NRAS’s association with DCIS and invasive breast cancer was assessed by Wilcoxon signed rank test. How NRAS levels correlated with basal biomarkers in the TMAs, as well as in patient datasets GSE59248 and GSE3369 was determined by Pearson correlation. Gene expression changes in cell line were assessed by RNA-seq. Results: Invasive breast cancers showed higher NRAS mRNA levels, as compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signature, lower ER, higher p53 protein levels, and higher Ki67 levels. We have shown previously that N-Ras is a driver for tumor growth in SUM102 cells, which is a DCIS-like cell line model displaying basal-like features. Here we found that NRAS-silencing in these cells induced a shift to a luminal gene expression pattern as determined by PAM50. Conclusions: These data suggest that the rise of N-RAS levels in DCIS can not only mark but also control the emergence of basal-like features leading to more aggressive tumor activities. Targeting N-Ras and/or its downstream pathway may prevent the emergence of basal invasive breast cancers. Citation Format: Ze-yi Zheng, Hanan Elsarraj, Yang Hong, Jonathan T. Lei, Meenakshi Anurag, Yichao Shen, Flora Lo, Long Feng, Zifan Zhao, Xiang H. Zhang, Fariba Behbod, Eric C. Chang. ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2979.
Abstract 5995: Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC)
Authors: Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Beverly Chigarira, Blake Nordblad, Vinay Mathew Thomas, Benjamin Haaland, Roberto Nussenzveig, Sumati Gupta, Neeraj Agarwal, Umang Swami, Benjamin L. Maughan
Journal: Cancer Research (2022)

Abstract Background: Presence of liver metastasis is associated with a poor prognosis in mUC. According to the prognostic model by Sonpavde et. al, post platinum treated mUC pts with liver metastasis had a 50% higher risk of death on immunotherapy compared to pts without liver metastasis (PMID 32552295). Herein, we hypothesize that pts with liver metastasis harbor a distinct tumor genomic landscape compared to pts without liver metastasis. Methods: In this IRB-approved retrospective study, mUC pts with and without liver metastasis at baseline and available tumor comprehensive genomic profiling (CGP) from a CLIA-certified laboratory were included. Variants of unknown significance and mutated genes present in ≤ 5% of pts were excluded. A Chi-square test was used to compare the frequency of mutated genes between both groups. The p-value was adjusted for false discovery, significance was preset at 0.25. Results: 114 pts were included. 16/114 pts had a liver metastasis. Median age was 69 and 67 years, male/female 12/4 and 72/26, smokers/non-smokers 6/10 and 46/52, for pts with and without liver metastasis respectively. The most frequent genomic alterations (GAs) were seen in TP53, CDKN2B and FGFR3. Pts with liver metastasis had significantly higher GAs in MYC (unadjusted p=0.009, adjusted p=0.24) compared to pts without liver metastasis. The median number of GAs per patient and the tumor mutation burden were not significantly different between groups. Conclusion: Our results indicate GAs in MYC are significantly enriched in pts with liver metastasis compared to those without liver metastasis. These hypothesis generating data require external validation. Genes Liver Metastasis: N=16 Non-Liver Metastasis: N=98 Adjusted P-value MYC 3(18.8%) 3(3.1%) 0.24 ERBB3 3(18.8%) 5(5.1%) 0.62 FGFR3 5(31.2%) 16(16.3%) 0.73 RICTOR 2(12.5%) 4(4.1%) 0.73 TP53 7(43.8%) 58(59.2%) 0.73 ERBB2 3(18.8%) 9(9.2%) 0.73 CDKN2B 7(43.8%) 31(31.6%) 0.73 ARID1A 3(18.8%) 21(21.4%) 0.90 RB1 3(18.8%) 24(24.5%) 0.90 KDM6A 2(12.5%) 19(19.4%) 0.90 Citation Format: Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Beverly Chigarira, Blake Nordblad, Vinay Mathew Thomas, Benjamin Haaland, Roberto Nussenzveig, Sumati Gupta, Neeraj Agarwal, Umang Swami, Benjamin L. Maughan. Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5995.
Abstract 930: Novel orthotopic pancreatic cancer cell lines derived from B6-KPC mice
Authors: Fang Zhu, Cunxiang Ju, Hongyan Sun, Weiwei Yu, Chao Ju, Shuai Li, Yunlong Jiang, Dongjing Jia, Steve Smith, Zhiying Li, Jing Zhao, Xiang Gao
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. B6-KPC mice ( LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre) generate spontaneous PDAC which could recapitulate the pathogenesis and genomic features of human PDAC. Although B6-KPC model is a wildly used for the exploration of the mechanisms of PDAC, some drawbacks of the model, such as long time for tumorigenesis, individual variation and difficulties in tumor observation, limit its application in cancer therapy. It is necessary to develop the pancreatic tumor cell lines from these models. In this study, we successfully established and well-characterized the luciferase-labled cell line mPAKPC-Luciferase. This cells carried the KrasG12D and Trp53R172H mutation. The orthotopic mPAKPC-Luciferase tumor model was well established by implanting tumor cell line into pancreas of B6 wild type mice and the tumor growth was traced by in vivo imaging. Moreover, Gemcitabine or combined with CD40 agonist presented significant tumor growth inhibition in B6 bearing mPAKPC-Luciferase orthotopic mouse models. While anti-PD1 or anti-OX40 had no anti-tumor effects in this model accordance with the low T cell infiltration of mPAKPC modle as a “cold” tumor. In addition, the immune profiling of this cell line showed highly expressed of potential therapeutic targets, including Claudin 18.2, CD47, CD73. Thus, mPAKPC-Luciferase cell lines are valuable models for the PDAC preclinical therapies. Citation Format: Fang Zhu, Cunxiang Ju, Hongyan Sun, Weiwei Yu, Chao Ju, Shuai Li, Yunlong Jiang, Dongjing Jia, Steve Smith, Zhiying Li, Jing Zhao, Xiang Gao. Novel orthotopic pancreatic cancer cell lines derived from B6-KPC mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 930.
Abstract 1888: Identification and optimization of novel small molecule modulators of immune checkpoint resistance with a unified representation space for genomic and chemical perturbations
Authors: Ashish Bhandari, Michael F. Cuccarese, Kevin Fales, Kiran Nadella, Rebecca Sarto Basso, Daria Beshnova, Hayley Donnella, Bahar Shamloo, Jacob Cooper, Imran Haque, Ron Alfa, Jacob Rinaldi
Journal: Cancer Research (2022)

Abstract Immune checkpoint inhibitors have revolutionized cancer treatment, producing a durable response consistent with immunologic memory in a subset of patients. However, the majority of patients demonstrate innate or acquired resistance that must be characterized and overcome to induce successful treatment. Advancements in human reverse translation and scaled in vivo CRISPR screening have uncovered novel molecular and genomic correlates of resistance, and promising druggable mechanisms - driven by highly complex interactions between tumor cells and the immune system. It is this core biology that must be disentangled to build the treatment paradigms of the future. Here we demonstrate a technique for massively parallel prioritization of new immuno-oncology hypotheses using industrial-scale experimentation and machine learning. Leveraging high-content imaging data from whole-genome CRISPR knockout and a library of &amp;gt;250,000 compounds, a deep learning model was trained to construct a batch-invariant low dimensional representation of each perturbation. Millions of perturbations in multiple cell types were embedded in a unified representation space that was leveraged to increase the rate of discovery, accelerate reverse translation, yield novel biological insights, and guide the advancement of lead molecular series through SAR. Here we highlight multiple discovery programs driven by inferred relationships between small molecules and gene knockout with translation from inference to in vivo efficacy. Specifically, we prioritize molecules with activity in STK11-deficient tumors and additional immune checkpoint sensitizers. Citation Format: Ashish Bhandari, Michael F. Cuccarese, Kevin Fales, Kiran Nadella, Rebecca Sarto Basso, Daria Beshnova, Hayley Donnella, Bahar Shamloo, Jacob Cooper, Imran Haque, Ron Alfa, Jacob Rinaldi. Identification and optimization of novel small molecule modulators of immune checkpoint resistance with a unified representation space for genomic and chemical perturbations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1888.
Abstract 1198: Discovering novel bispecific antibody targets through the mining of large-scale bulk and single cell RNA-seq databases
Authors: Eugene Chekalin, Shreya Paithankar, Bin Chen
Journal: Cancer Research (2022)

Abstract Bispecific antibodies (bsAbs) that bind two distinct surface proteins in cancer cells are emerging as an appealing therapeutic strategy in cancer immunotherapy. Among thousands of surface proteins, experimentally identifying the best target pairs that are expressed only in cancer cells, but not in normal cells, is costly and time-consuming. The open bulk RNASeq and single-cell (sc)RNASeq offers a great resource to identify novel bispecific targets. Bulk RNASeq has been widely explored to identify therapeutic targets and biomarkers, resulting in voluminous data for various cancers and normal tissues, but the mixture of cell types in bulk RNASeq could not characterize the precise expression of targets in cancer cells, resulting in considerable false positives. scRNASeq provides a high resolution of target expression in individual cells, however, the challenges in solving the dropout issue and cell type classification hinder the direct use of scRNASeq in bsAbs target identification. Utilizing the OCTAD database consisting of over 20,000 bulk RNASeq samples, we proposed an approach that identifies target pairs that separate tumors from healthy the most, taking into account cluster heterogeneity, the distance between tumors and healthy as well as the angle between potential markers. Among the top pairs in Hepatocellular Carcinoma (HCC), CD33~PLVAP, for example, was a false positive because CD33 is myeloid and lymphoid cell lineage-specific. We thus assembled a scRNAseq database of healthy vital organs containing 39361 cells to aid selection. By comparing their expression with the expression of 18000 malignant cells predicted from 72000 cells of eight HCC samples, we identified target pairs that mostly express on the surface of the malignant HCC cells and had low or zero expression in vital organs. The most promising marker pair was GPC3~MUC13, presenting on the surface of over 30% of malignant HCC cells, with very low expression in vital organs. We further developed an R package to navigate the bsAbs target selection from open bulk RNASeq and scRNASeq. Citation Format: Eugene Chekalin, Shreya Paithankar, Bin Chen. Discovering novel bispecific antibody targets through the mining of large-scale bulk and single cell RNA-seq databases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1198.
Abstract 2954: Chromatin accessibility dynamics in CDK4/6 inhibitor-induced senescence
Authors: Justin Rendleman, Joanna Yeung, Nicole Pagane, Irene Duba, Andrew Scortea, Andrew Koff, Viviana I. Risca
Journal: Cancer Research (2022)

Abstract Liposarcomas are a rare cancer that often undergo amplification of the 12q13-15 locus, which includes the gene encoding the cyclin-dependent kinase CDK4; CDK4/6 inhibitors therefore offer a promising targeted therapy to halt proliferation in these tumors where therapeutic options are scarce once surgical resection is no longer possible. CDK4/6 inhibition can lead to either reversible or irreversible exit from the cell cycle (quiescence or senescence, respectively), but the underlying mechanisms are not well understood. Applying ATAC-seq in a liposarcoma cell line model of therapy-induced senescence, we have assayed alterations in the chromatin landscape that arise in response to CDK4/6 inhibitor treatment to identify epigenetic changes that drive this cell fate decision. Additionally, we have compared this with cells that undergo senescence due to DNA damage induced by the drug doxorubicin, an anthracycline that is the standard first-line chemotherapy for liposarcoma. In CDK4/6 inhibition, we identified dynamic patterns of accessibility as cells transition from quiescence to senescence over 28 days of treatment. NF-kB motifs in promoter-proximal regions displayed increased accessibility as cells commit to the senescence state, and ATAC-seq peaks with AP-1 transcription factor family motifs exhibit dynamic accessibility. We characterized the DNA damage response by gamma-H2AX and 53BP1 immunofluorescence and found that for CDK4/6 inhibition there is minimal DNA damage and only at late senescence time points, in marked contrast with doxorubicin treatment. We observed differences in accessibility between CDK4/6 inhibitor- and doxorubicin-induced senescence in a region on chromosome 6 that contains the gene FRK. This gene encodes a tyrosine kinase in the Src family that negatively regulates cell proliferation and has been implicated as a tumor suppressor through upregulation of p21, which may reinforce restriction of phosphorylation on Rb in parallel with CDK4/6 inhibition. These findings provide further evidence of the epigenetic impact of CDK4/6 inhibitors in cancer cells, and highlight shared and specific mechanisms that lead to therapy-induced senescence. Citation Format: Justin Rendleman, Joanna Yeung, Nicole Pagane, Irene Duba, Andrew Scortea, Andrew Koff, Viviana I. Risca. Chromatin accessibility dynamics in CDK4/6 inhibitor-induced senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2954.
Abstract 1653: Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma
Authors: Maria Teresa Bilotta, Antonella Antignani, David J. Fitzgerald
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) represents a highly complex compartment that includes cancer cells, non-hematopoietic stromal cells, extracellular matrix, lymphocytes, and myeloid cells. Interactions between these populations and the factors they secrete play critical roles in determining the host response to cancer. Conventional mouse xenograft models of human cancer lack a competent immune system. Indeed, the use of xenograft models often fail to translate into effective human treatments. Classical Hodgkin Lymphoma (HL) is characterized by the presence in the lymphonodes of abnormal Reed-Sternberg cells, and many cell types beyond them, in particular Treg. To reconstitute a more complete TME, human PBMCs were injected into NSG mice bearing L540 HL cells. Then over time the presence of various human CD45+ cell populations were monitored within the tumor mass, in the spleen and in circulation. The goal of our study is to gain a better understanding of the interaction of the immune cell infiltrates into the HL microenvironment, leading ultimately to improved treatment outcomes. Lymphocyte infiltration into the tumor showed a predominance of human CD3+ cells (T lymphocytes), even if in the spleen we found both human T and B cells, indicating that this model might help us design more effective treatments. To reflect the immune reconstitution of these animals and its interaction with tumor and to better understand the capacity of T lymphocytes to kill the cancer cells, we evaluated the production of human IFN- gamma. We found an increase of IFN- gamma in L540-bearing mice reconstituted with hPBMCs compared to the mice without them, indicating a certain functionality of the T cells in these tumors. Moreover, in this model, the immune reconstitution did not decrease tumor growth, rendering this model useful for the study of biotherapeutic and immunotherapeutic studies. The model might be useful to study the anticancer therapy at a preclinical level because a remodeling of the anti-tumor immune response can be evaluated. Citation Format: Maria Teresa Bilotta, Antonella Antignani, David J. Fitzgerald. Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1653.
Enhancement of Lymphangiogenesis by Human Mesenchymal Stem Cell Sheet
Authors: Wenkai Jia, Weilue He, Guifang Wang, Jeremy Goldman, Feng Zhao
Journal: Advanced Healthcare Materials (2022)

Preparation of human mesenchymal stem cell (hMSC) suspension for lymphedema treatment relies on conventional enzymatic digestion methods, which severely disrupts cell-cell and cell-extracellular matrix (ECM) connections, and drastically impairs cell retention and engraftment after transplantation. The objective of the present study is to evaluate the ability of hMSC-secreted ECM to augment lymphangiogenesis by using an in vitro coculturing model of hMSC sheets with lymphatic endothelial cells (LECs) and an in vivo mouse tail lymphedema model. Results demonstrate that the hMSC-secreted ECM augments the formation of lymphatic capillary-like structure by a factor of 1.2-3.6 relative to the hMSC control group, by serving as a prolymphangiogenic growth factor reservoir and facilitating cell regenerative activities. hMSC-derived ECM enhances MMP-2 mediated matrix remodeling, increases the synthesis of collagen IV and laminin, and promotes lymphatic microvessel-like structure formation. The injection of rat MSC sheet fragments into a mouse tail lymphedema model confirms the benefits of the hMSC-derived ECM by stimulating lymphangiogenesis and wound closure.
A TEAM Approach to Diversity, Equity, and Inclusion in Gastroenterology and Hepatology
Authors: Renee Williams, Pascale M. White, Sophie Balzora, Valerie Antoine-Gustave, Adjoa Anyane-Yeboa, Rotonya M. Carr, Darrell M. Gray, Alexandra Guillaume, Ugonna Iroku, Rachel B. Issaka, Folasade P. May
Journal: Clinical Gastroenterology and Hepatology (2022)